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Valenzuela G, Contreras HR, Marcelain K, Burotto M, González-Montero J. Understanding microRNA-Mediated Chemoresistance in Colorectal Cancer Treatment. Int J Mol Sci 2025; 26:1168. [PMID: 39940936 PMCID: PMC11818086 DOI: 10.3390/ijms26031168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2025] [Revised: 01/23/2025] [Accepted: 01/27/2025] [Indexed: 02/16/2025] Open
Abstract
Colorectal cancer (CRC) remains the second most lethal cancer worldwide, with incidence rates expected to rise substantially by 2040. Although biomarker-driven therapies have improved treatment, responses to standard chemotherapeutics, such as 5-fluorouracil (5-FU), oxaliplatin, and irinotecan, vary considerably. This clinical heterogeneity emphasizes the urgent need for novel biomarkers that can guide therapeutic decisions and overcome chemoresistance. microRNAs (miRNAs) have emerged as key post-transcriptional regulators that critically influence chemotherapy responses. miRNAs orchestrate post-transcriptional gene regulation and modulate diverse pathways linked to chemoresistance. They influence drug transport by regulating ABC transporters and affect metabolic enzymes like thymidylate synthase (TYMS). These activities shape responses to standard CRC chemotherapy agents. Furthermore, miRNAs can regulate the epithelial-mesenchymal transition (EMT). The miR-200 family (e.g., miR-200c and miR-141) can reverse EMT phenotypes, restoring chemosensitivity. Additionally, miRNAs like miR-19a and miR-625-3p show predictive value for chemotherapy outcomes. Despite these promising findings, the clinical translation of miRNA-based biomarkers faces challenges, including methodological inconsistencies and the dynamic nature of miRNA expression, influenced by the tumor microenvironment. This review highlights the critical role of miRNAs in elucidating chemoresistance mechanisms and their promise as biomarkers and therapeutic targets in CRC, paving the way for a new era of precision oncology.
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Affiliation(s)
- Guillermo Valenzuela
- Basic and Clinical Oncology Department, Faculty of Medicine, University of Chile, Santiago 8350499, Chile; (G.V.); (H.R.C.); (K.M.)
- Center for Cancer Prevention and Control (CECAN), Santiago 8380453, Chile
| | - Héctor R. Contreras
- Basic and Clinical Oncology Department, Faculty of Medicine, University of Chile, Santiago 8350499, Chile; (G.V.); (H.R.C.); (K.M.)
- Center for Cancer Prevention and Control (CECAN), Santiago 8380453, Chile
| | - Katherine Marcelain
- Basic and Clinical Oncology Department, Faculty of Medicine, University of Chile, Santiago 8350499, Chile; (G.V.); (H.R.C.); (K.M.)
- Center for Cancer Prevention and Control (CECAN), Santiago 8380453, Chile
| | - Mauricio Burotto
- Bradford Hill Clinical Research Center, Santiago 8380453, Chile;
| | - Jaime González-Montero
- Basic and Clinical Oncology Department, Faculty of Medicine, University of Chile, Santiago 8350499, Chile; (G.V.); (H.R.C.); (K.M.)
- Center for Cancer Prevention and Control (CECAN), Santiago 8380453, Chile
- Bradford Hill Clinical Research Center, Santiago 8380453, Chile;
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Pan Y, Wu M, Cai H. Role of ABCC5 in cancer drug resistance and its potential as a therapeutic target. Front Cell Dev Biol 2024; 12:1446418. [PMID: 39563862 PMCID: PMC11573773 DOI: 10.3389/fcell.2024.1446418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Accepted: 10/22/2024] [Indexed: 11/21/2024] Open
Abstract
Over 90% of treatment failures in cancer therapy can be attributed to multidrug resistance (MDR), which can develop intracellularly or through various routes. Numerous pathways contribute to treatment resistance in cancer, but one of the most significant pathways is intracellular drug efflux and reduced drug concentrations within cells, which are controlled by overexpressed drug efflux pumps. As a member of the family of ABC transporter proteins, ABCC5 (ATP Binding Cassette Subfamily C Member 5) reduces the intracellular concentration of a drug and its subsequent effectiveness using an ATP-dependent method to pump the drug out of the cell. Numerous studies have demonstrated that ABCC5 is strongly linked to both poor prognosis and poor treatment response. In addition, elevated ABCC5 expression is noted in a wide variety of malignancies. Given that ABCC5 is regulated by several pathways in a broad range of cancer types, it is a prospective target for cancer treatment. This review examined the expression, structure, function, and role of ABCC5 in various cancer types.
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Affiliation(s)
- Yinlong Pan
- Department of Emergency, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Mengmeng Wu
- Department of Anesthesiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Huazhong Cai
- Department of Emergency, Affiliated Hospital of Jiangsu University, Zhenjiang, China
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3
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Ramoni D, Carbone F, Montecucco F. Navigating the autophagic landscape: Epigenetic modulation in gastrointestinal cancer. World J Gastroenterol 2024; 30:3628-3634. [PMID: 39192999 PMCID: PMC11346161 DOI: 10.3748/wjg.v30.i31.3628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 07/18/2024] [Accepted: 07/23/2024] [Indexed: 08/13/2024] Open
Abstract
This editorial comments on the manuscript by Chang et al, focusing on the still elusive interplay between epigenetic regulation and autophagy in gastrointestinal diseases, particularly cancer. Autophagy, essential for cellular homeostasis, exhibits diverse functions ranging from cell survival to death, and is particularly implicated in physiological gastrointestinal cell functions. However, its role in pathological backgrounds remains intricate and context-dependent. Studies underscore the dual nature of autophagy in cancer, where its early suppressive effects in early stages are juxtaposed with its later promotion, contributing to chemoresistance. This discrepancy is attributed to the dysregulation of autophagy-related genes and their intricate involvement in cellular processes. Epigenetic modifications and regulations of gene expression, including non-coding RNAs (ncRNAs), emerge as critical players in exerting regulatory control over autophagy flux, influencing treatment responses and tumor progression. Targeting epigenetic mechanisms and improving strategies involving the inhibition or induction of autophagy through pharmacological or genetic means present potential avenues to sensitize tumor cells to chemotherapy. Additionally, nanocarrier-based delivery of ncRNAs offers innovative therapeutic approaches. Understanding the intricate interaction between autophagy and ncRNA regulation opens avenues for the development of targeted therapies, thereby improving the prognosis of gastrointestinal malignancies with poor outcomes.
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Affiliation(s)
- Davide Ramoni
- Department of Internal Medicine, University of Genoa, Genoa 16132, Italy
| | - Federico Carbone
- Department of Internal Medicine, University of Genoa and IRCSS Policlinico San Martino, Genoa 16132, Italy
| | - Fabrizio Montecucco
- Department of Internal Medicine, University of Genoa and IRCSS Policlinico San Martino, Genoa 16132, Italy
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Sheikhnia F, Maghsoudi H, Majidinia M. The Critical Function of microRNAs in Developing Resistance against 5- Fluorouracil in Cancer Cells. Mini Rev Med Chem 2024; 24:601-617. [PMID: 37642002 DOI: 10.2174/1389557523666230825144150] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 07/06/2023] [Accepted: 07/13/2023] [Indexed: 08/31/2023]
Abstract
Although there have been significant advancements in cancer treatment, resistance and recurrence in patients make it one of the leading causes of death worldwide. 5-fluorouracil (5-FU), an antimetabolite agent, is widely used in treating a broad range of human malignancies. The cytotoxic effects of 5-FU are mediated by the inhibition of thymidylate synthase (TYMS/TS), resulting in the suppression of essential biosynthetic activity, as well as the misincorporation of its metabolites into RNA and DNA. Despite its huge benefits in cancer therapy, the application of 5-FU in the clinic is restricted due to the occurrence of drug resistance. MicroRNAs (miRNAs) are small, non-coding RNAs that act as negative regulators in many gene expression processes. Research has shown that changes in miRNA play a role in cancer progression and drug resistance. This review examines the role of miRNAs in 5-FU drug resistance in cancers.
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Affiliation(s)
- Farhad Sheikhnia
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
- Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Hossein Maghsoudi
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
- Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Maryam Majidinia
- Solid Tumor Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran
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5
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Hussen BM, Abdullah ST, Abdullah SR, Younis YM, Hidayat HJ, Rasul MF, Mohamadtahr S. Exosomal non-coding RNAs: Blueprint in colorectal cancer metastasis and therapeutic targets. Noncoding RNA Res 2023; 8:615-632. [PMID: 37767111 PMCID: PMC10520679 DOI: 10.1016/j.ncrna.2023.09.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 09/08/2023] [Accepted: 09/08/2023] [Indexed: 09/29/2023] Open
Abstract
Colorectal cancer (CRC) is ranked as the world's third-most prevalent cancer, and metastatic CRC considerably increases cancer-related fatalities globally. A number of complex mechanisms that are strictly controlled at the molecular level are involved in metastasis, which is the primary reason for death in people with CRC. Recently, it has become clear that exosomes, which are small extracellular vesicles released by non-tumorous and tumorigenic cells, play a critical role as communication mediators among tumor microenvironment (TME). To facilitate communication between the TME and cancer cells, non-coding RNAs (ncRNAs) play a crucial role and are recognized as potent regulators of gene expression and cellular processes, such as metastasis and drug resistance. NcRNAs are now recognized as potent regulators of gene expression and many hallmarks of cancer, including metastasis. Exosomal ncRNAs, like miRNAs, circRNAs, and lncRNAs, have been demonstrated to influence a number of cellular mechanisms that contribute to CRC metastasis. However, the molecular mechanisms that link exosomal ncRNAs with CRC metastasis are not well understood. This review highlights the essential roles that exosomal ncRNAs play in the progression of CRC metastatic disease and explores the therapeutic choices that are open to patients who have CRC metastases. However, exosomal ncRNA treatment strategy development is still in its early phases; consequently, additional investigation is required to improve delivery methods and find novel therapeutic targets as well as confirm the effectiveness and safety of these therapies in preclinical and clinical contexts.
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Affiliation(s)
- Bashdar Mahmud Hussen
- Department of Biomedical Sciences, College of Science, Cihan University-Erbil, Erbil, Kurdistan Region, 44001, Iraq
- Department of Clinical Analysis, College of Pharmacy, Hawler Medical University, Kurdistan Region, Erbil, Iraq
| | - Sara Tharwat Abdullah
- Department of Pharmacology and Toxicology, College of Pharmacy, Hawler Medical University, Erbil, Iraq
| | - Snur Rasool Abdullah
- Medical Laboratory Science, College of Health Sciences, Lebanese French University, Kurdistan Region, Erbil, Iraq
| | - Yousif Mohammed Younis
- Department of Nursing, College of Nursing, Lebanese French University, Kurdistan Region, Erbil, Iraq
| | - Hazha Jamal Hidayat
- Department of Biology, College of Education, Salahaddin University-Erbil, Kurdistan Region, Iraq
| | - Mohammed Fatih Rasul
- Department of Pharmaceutical Basic Science, Faculty of Pharmacy, Tishk International University, Erbil, Kurdistan Region, Iraq
| | - Sayran Mohamadtahr
- Department of Clinical Analysis, College of Pharmacy, Hawler Medical University, Kurdistan Region, Erbil, Iraq
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6
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Ding P, Gao Y, Wang J, Xiang H, Zhang C, Wang L, Ji G, Wu T. Progress and challenges of multidrug resistance proteins in diseases. Am J Cancer Res 2022; 12:4483-4501. [PMID: 36381332 PMCID: PMC9641395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 10/09/2022] [Indexed: 06/16/2023] Open
Abstract
Chemotherapy remains the first choice for patients with advanced cancers when other treatments are ineffective. Multidrug resistance (MDR) is an unavoidable factor that negatively affects the effectiveness of cancer chemotherapy drugs. Researchers are trying to reduce MDR, improve the effectiveness of chemotherapeutic drugs, and alleviate patient suffering to positively contribute to disease treatment. MDR also occurs in inflammation and genetic disorders, which increases the difficulty of clinically beneficial treatments. The ATP-binding cassette (ABC) is an active transporter that plays an important role in the barrier and secretory functions of many normal cells. As the C subfamily in the ABC family, multidrug resistance proteins (MRPs/ABCCs) export a variety of antitumour drugs and are expressed in a variety of cancers. The present review summarises the role of MRPs in cancer and other diseases and recent research progress of MRP inhibitors to better examine the mechanism and function of MRPs, and establish a good relationship with clinical treatment.
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Affiliation(s)
- Peilun Ding
- Department of Hepatology, Longhua Hospital, Shanghai University of Traditional Chinese MedicineShanghai 200032, China
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese MedicineShanghai 201203, China
| | - Ying Gao
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese MedicineShanghai 201203, China
| | - Junmin Wang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese MedicineShanghai 201203, China
| | - Hongjiao Xiang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese MedicineShanghai 201203, China
| | - Caiyun Zhang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese MedicineShanghai 201203, China
| | - Lei Wang
- Department of Hepatology, Longhua Hospital, Shanghai University of Traditional Chinese MedicineShanghai 200032, China
| | - Guang Ji
- Institute of Digestive Disease, Longhua Hospital, Shanghai University of Traditional Chinese MedicineShanghai 200032, China
| | - Tao Wu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese MedicineShanghai 201203, China
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7
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Jiang Y, Zhao H, Chen Y, Li K, Li T, Chen J, Zhang B, Guo C, Qing L, Shen J, Liu X, Gu P. Exosomal long noncoding RNA HOXD-AS1 promotes prostate cancer metastasis via miR-361-5p/FOXM1 axis. Cell Death Dis 2021; 12:1129. [PMID: 34864822 PMCID: PMC8643358 DOI: 10.1038/s41419-021-04421-0] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 11/16/2021] [Accepted: 11/24/2021] [Indexed: 12/22/2022]
Abstract
Development of distant metastasis is the main cause of deaths in prostate cancer (PCa) patients. Understanding the mechanism of PCa metastasis is of utmost importance to improve its prognosis. The role of exosomal long noncoding RNA (lncRNA) has been reported not yet fully understood in the metastasis of PCa. Here, we discovered an exosomal lncRNA HOXD-AS1 is upregulated in castration resistant prostate cancer (CRPC) cell line derived exosomes and serum exosomes from metastatic PCa patients, which correlated with its tissue expression. Further investigation confirmed exosomal HOXD-AS1 promotes prostate cancer cell metastasis in vitro and in vivo by inducing metastasis associated phenotype. Mechanistically exosomal HOXD-AS1 was internalized directly by PCa cells, acting as competing endogenous RNA (ceRNA) to modulate the miR-361-5p/FOXM1 axis, therefore promoting PCa metastasis. In addition, we found that serum exosomal HOXD-AS1 was upregulated in metastatic PCa patients, especially those with high volume disease. And it is correlated closely with Gleason Score, distant and nodal metastasis, Prostatic specific antigen (PSA) recurrence free survival, and progression free survival (PFS). This sheds a new insight into the regulation of PCa distant metastasis by exosomal HOXD-AS1 mediated miR-361-5p/FOXM1 axis, and provided a promising liquid biopsy biomarker to guide the detection and treatment of metastatic PCa.
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Affiliation(s)
- Yongming Jiang
- grid.285847.40000 0000 9588 0960Department of Urology, The 1st Affiliated Hospital of Kunming Medical University, Kunming, 650032 China ,grid.415444.40000 0004 1800 0367Department of Urology, The 2nd Affiliated Hospital of Kunming Medical University, Kunming, 650101 China
| | - Hui Zhao
- grid.285847.40000 0000 9588 0960Department of Urology, The 1st Affiliated Hospital of Kunming Medical University, Kunming, 650032 China ,Yunnan Province Clinical Research Center for Chronic Kidney Disease, Kunming, 650032 China
| | - Yuxiao Chen
- grid.285847.40000 0000 9588 0960Department of Urology, The 1st Affiliated Hospital of Kunming Medical University, Kunming, 650032 China ,Yunnan Province Clinical Research Center for Chronic Kidney Disease, Kunming, 650032 China
| | - Kangjian Li
- Department of Urology, The Second People’s Hospital of Qujing City, Qujing City, Yunnan Province 655000 China
| | - Tianjie Li
- grid.285847.40000 0000 9588 0960Department of Urology, The 1st Affiliated Hospital of Kunming Medical University, Kunming, 650032 China
| | - Jianheng Chen
- grid.285847.40000 0000 9588 0960Department of Urology, The 1st Affiliated Hospital of Kunming Medical University, Kunming, 650032 China ,Yunnan Province Clinical Research Center for Chronic Kidney Disease, Kunming, 650032 China
| | - Baiyu Zhang
- grid.285847.40000 0000 9588 0960Department of Urology, The 1st Affiliated Hospital of Kunming Medical University, Kunming, 650032 China ,Yunnan Province Clinical Research Center for Chronic Kidney Disease, Kunming, 650032 China
| | - Caifen Guo
- grid.285847.40000 0000 9588 0960Department of Urology, The 1st Affiliated Hospital of Kunming Medical University, Kunming, 650032 China
| | - Liangliang Qing
- grid.285847.40000 0000 9588 0960Department of Urology, The 1st Affiliated Hospital of Kunming Medical University, Kunming, 650032 China
| | - Jihong Shen
- grid.285847.40000 0000 9588 0960Department of Urology, The 1st Affiliated Hospital of Kunming Medical University, Kunming, 650032 China ,Yunnan Province Clinical Research Center for Chronic Kidney Disease, Kunming, 650032 China
| | - Xiaodong Liu
- Department of Urology, The 1st Affiliated Hospital of Kunming Medical University, Kunming, 650032, China. .,Yunnan Province Clinical Research Center for Chronic Kidney Disease, Kunming, 650032, China.
| | - Peng Gu
- Department of Urology, The 1st Affiliated Hospital of Kunming Medical University, Kunming, 650032, China. .,Yunnan Province Clinical Research Center for Chronic Kidney Disease, Kunming, 650032, China.
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Azwar S, Seow HF, Abdullah M, Faisal Jabar M, Mohtarrudin N. Recent Updates on Mechanisms of Resistance to 5-Fluorouracil and Reversal Strategies in Colon Cancer Treatment. BIOLOGY 2021; 10:854. [PMID: 34571731 PMCID: PMC8466833 DOI: 10.3390/biology10090854] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 08/04/2020] [Accepted: 08/11/2020] [Indexed: 02/06/2023]
Abstract
5-Fluorouracil (5-FU) plus leucovorin (LV) remain as the mainstay standard adjuvant chemotherapy treatment for early stage colon cancer, and the preferred first-line option for metastatic colon cancer patients in combination with oxaliplatin in FOLFOX, or irinotecan in FOLFIRI regimens. Despite treatment success to a certain extent, the incidence of chemotherapy failure attributed to chemotherapy resistance is still reported in many patients. This resistance, which can be defined by tumor tolerance against chemotherapy, either intrinsic or acquired, is primarily driven by the dysregulation of various components in distinct pathways. In recent years, it has been established that the incidence of 5-FU resistance, akin to multidrug resistance, can be attributed to the alterations in drug transport, evasion of apoptosis, changes in the cell cycle and DNA-damage repair machinery, regulation of autophagy, epithelial-to-mesenchymal transition, cancer stem cell involvement, tumor microenvironment interactions, miRNA dysregulations, epigenetic alterations, as well as redox imbalances. Certain resistance mechanisms that are 5-FU-specific have also been ascertained to include the upregulation of thymidylate synthase, dihydropyrimidine dehydrogenase, methylenetetrahydrofolate reductase, and the downregulation of thymidine phosphorylase. Indeed, the successful modulation of these mechanisms have been the game plan of numerous studies that had employed small molecule inhibitors, plant-based small molecules, and non-coding RNA regulators to effectively reverse 5-FU resistance in colon cancer cells. It is hoped that these studies would provide fundamental knowledge to further our understanding prior developing novel drugs in the near future that would synergistically work with 5-FU to potentiate its antitumor effects and improve the patient's overall survival.
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Affiliation(s)
- Shamin Azwar
- Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Malaysia; (S.A.); (H.F.S.); (M.A.)
| | - Heng Fong Seow
- Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Malaysia; (S.A.); (H.F.S.); (M.A.)
| | - Maha Abdullah
- Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Malaysia; (S.A.); (H.F.S.); (M.A.)
| | - Mohd Faisal Jabar
- Department of Surgery, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Malaysia;
| | - Norhafizah Mohtarrudin
- Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Malaysia; (S.A.); (H.F.S.); (M.A.)
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Ghafouri-Fard S, Abak A, Tondro Anamag F, Shoorei H, Fattahi F, Javadinia SA, Basiri A, Taheri M. 5-Fluorouracil: A Narrative Review on the Role of Regulatory Mechanisms in Driving Resistance to This Chemotherapeutic Agent. Front Oncol 2021; 11:658636. [PMID: 33954114 PMCID: PMC8092118 DOI: 10.3389/fonc.2021.658636] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 03/24/2021] [Indexed: 12/14/2022] Open
Abstract
5-fluorouracil (5-FU) is among the mostly administrated chemotherapeutic agents for a wide variety of neoplasms. Non-coding RNAs have a central impact on the determination of the response of patients to 5-FU. These transcripts via modulation of cancer-related pathways, cell apoptosis, autophagy, epithelial-mesenchymal transition, and other aspects of cell behavior can affect cell response to 5-FU. Modulation of expression levels of microRNAs or long non-coding RNAs may be a suitable approach to sensitize tumor cells to 5-FU treatment via modulating multiple biological signaling pathways such as Hippo/YAP, Wnt/β-catenin, Hedgehog, NF-kB, and Notch cascades. Moreover, there is an increasing interest in targeting these transcripts in various kinds of cancers that are treated by 5-FU. In the present article, we provide a review of the function of non-coding transcripts in the modulation of response of neoplastic cells to 5-FU.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Dental Research Center, Research Institute for Dental Sciences, Dental School, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Atefe Abak
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Hamed Shoorei
- Department of Anatomical Sciences, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Faranak Fattahi
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, United States
- Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, United States
| | - Seyed Alireza Javadinia
- Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran
| | - Abbas Basiri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Taheri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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10
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Micallef I, Baron B. The Mechanistic Roles of ncRNAs in Promoting and Supporting Chemoresistance of Colorectal Cancer. Noncoding RNA 2021; 7:24. [PMID: 33807355 PMCID: PMC8103280 DOI: 10.3390/ncrna7020024] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 03/03/2021] [Accepted: 03/29/2021] [Indexed: 12/12/2022] Open
Abstract
Colorectal Cancer (CRC) is one of the most common gastrointestinal malignancies which has quite a high mortality rate. Despite the advances made in CRC treatment, effective therapy is still quite challenging, particularly due to resistance arising throughout the treatment regimen. Several studies have been carried out to identify CRC chemoresistance mechanisms, with research showing different signalling pathways, certain ATP binding cassette (ABC) transporters and epithelial mesenchymal transition (EMT), among others to be responsible for the failure of CRC chemotherapies. In the last decade, it has become increasingly evident that certain non-coding RNA (ncRNA) families are involved in chemoresistance. Research investigations have demonstrated that dysregulation of microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) contribute towards promoting resistance in CRC via different mechanisms. Considering the currently available data on this phenomenon, a better understanding of how these ncRNAs participate in chemoresistance can lead to suitable solutions to overcome this problem in CRC. This review will first focus on discussing the different mechanisms of CRC resistance identified so far. The focus will then shift onto the roles of miRNAs, lncRNAs and circRNAs in promoting 5-fluorouracil (5-FU), oxaliplatin (OXA), cisplatin and doxorubicin (DOX) resistance in CRC, specifically using ncRNAs which have been recently identified and validated under in vivo or in vitro conditions.
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Affiliation(s)
| | - Byron Baron
- Centre for Molecular Medicine and Biobanking, University of Malta, MSD2080 Msida, Malta;
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11
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Elucidation of underlying molecular mechanism of 5-Fluorouracil chemoresistance and its restoration using fish oil in experimental colon carcinoma. Mol Cell Biochem 2021; 476:1517-1527. [PMID: 33392922 DOI: 10.1007/s11010-020-03999-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 11/20/2020] [Indexed: 02/07/2023]
Abstract
Latest strategies for cancer treatment primarily focus on the use of chemosensitizers to enhance therapeutic outcome. N-3 PUFAs have emerged as the strongest candidate for the prevention of colorectal cancer (CRC). Our previous studies have demonstrated that fish oil (FO) rich in n-3 PUFAs not only increased therapeutic potential of 5-Fluorouracil(5-FU) in colon cancer but also ameliorated its toxicity. Henceforth, the present study is designed to elucidate mechanistic insights of FO as a chemosensitizer to circumvent drug resistance in experimental colon carcinoma. The colon cancer was induced by 1,2-dimethylhydrazine(DMH)/dextran sulfate sodium(DSS) in male Balb/c mice and these animals were treated with 5-FU(12.5 mg/kg b.w.), FO(0.2 ml), or 5-FU + FO(12.5 mg/kg b.w + 0.2 ml) orally for 14 days. The molecular mechanism of overcoming 5-FU resistance using FO in colon cancer was delineated by estimating expression of cancer stem cell markers using flowcytometric method and drug transporters by immunohistochemistry and immunoblotting. Additionally, distribution profile of 5-FU and its cytotoxic metabolite, 5-FdUMP at target(colon), and non-target sites (serum, kidney, liver, spleen) was assessed using high-performance liquid chromatography(HPLC) method. The observations revealed that expression of CSCs markers was remarkably reduced after using fish oil along with 5-FU in carcinogen-treated animals. Interestingly, the use of FO alongwith 5-FU also significantly declined the expression of drug transporters (ABCB1,ABCC5) and consequently resulted in an increased cellular uptake of 5-FU and its metabolite, 5-FdUMP at target site (colon). It could be possibly associated with change in permeability of cell membrane owing to the alteration in membrane fluidity. The present study revealed the mechanistic insights of FO as a MDR revertant which successfully restored 5-FU-mediated chemoresistance in experimental colon carcinoma.
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Liu AG, Pang YY, Chen G, Wu HY, He RQ, Dang YW, Huang ZG, Zhang R, Ma J, Yang LH. Downregulation of miR-199a-3p in Hepatocellular Carcinoma and Its Relevant Molecular Mechanism via GEO, TCGA Database and In Silico Analyses. Technol Cancer Res Treat 2020; 19:1533033820979670. [PMID: 33327879 PMCID: PMC7750904 DOI: 10.1177/1533033820979670] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Existing reports have demonstrated that miR-199a-3p plays a role as a tumor suppressor in a variety of human cancers. This study aims to further validate the expression of miR-199a-3p in HCC and to explore its underlying mechanisms by using multiple data sets. Chip data or sequencing data and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were integrated to assess the expression of miR-199a-3p in HCC. The potential targets and transcription factor regulatory network of miR-199a-3p in HCC were determined and possible biological mechanism of miR-199a-3p was analyzed with bioinformatics methods. In the results, miR-199a-3p expression was significantly lower in HCC tissues compared to normal tissues according to chip data or sequencing data and qRT-PCR. Moreover, 455 targets of miR-199a-3p were confirmed, and these genes were involved in the PI3K-Akt signaling pathway, pathways in cancer, and focal adhesions. LAMA4 was considered a key target of miR-199a-3p. In CMTCN, 11 co-regulatory pairs, 3 TF-FFLs, and 2 composite-FFLs were constructed. In conclusion, miR-199a-3p was down regulated in HCC and LAMA4 may be a potential target of miR-199a-3p in HCC.
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Affiliation(s)
- An-Gui Liu
- Department of Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Yu-Yan Pang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Gang Chen
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Hua-Yu Wu
- Departments of Cell Biology and Genetics, School of Pre-clinical Medicine, Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Rong-Quan He
- Department of Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Yi-Wu Dang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Zhi-Guang Huang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Rui Zhang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Jie Ma
- Department of Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China.,Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Li-Hua Yang
- Department of Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
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Zhang W, Liao K, Liu D. MicroRNA‑744‑5p is downregulated in colorectal cancer and targets SEPT2 to suppress the malignant phenotype. Mol Med Rep 2020; 23:54. [PMID: 33200802 PMCID: PMC7705998 DOI: 10.3892/mmr.2020.11692] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 08/28/2020] [Indexed: 12/13/2022] Open
Abstract
MicroRNA (miR)‑744‑5p serves a pivotal role in the progression of multiple cancers; however, the function of miR‑744‑5p in colorectal cancer (CRC) remains largely unknown. In the present study, the effects of miR‑744‑5p on the progression of CRC were analyzed and the mechanisms involved were investigated. It was revealed that miR‑744‑5p was frequently downregulated in CRC tissues and cell lines. Overexpression of miR‑744‑5p significantly inhibited the proliferation, colony formation, and promoted the apoptosis of CRC cells. Bioinformatics analysis revealed that Septin 2 (SEPT2) was a potential target of miR‑744‑5p. miR‑744‑5p bound the 3'‑untranslated region (UTR) of SEPT2 and reduced the level of SEPT2 in CRC cells. A negative correlation between the expression of miR‑744‑5p and SEPT2 was observed in CRC tissues. Overexpression of SEPT2 counteracted the suppressive effect of miR‑744‑5p on the proliferation and apoptosis of CRC cells. Collectively, these data demonstrated the functional mechanism of miR‑744‑5p by targeting SEPT2, which suggested miR‑744‑5p as a potential target for the treatment of patients with CRC.
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Affiliation(s)
- Wei Zhang
- Department of General Surgery, People's Hospital of Yichun City, Yichun, Jiangxi 336000, P.R. China
| | - Kai Liao
- Department of General Surgery, People's Hospital of Yichun City, Yichun, Jiangxi 336000, P.R. China
| | - Dongning Liu
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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Xue L, Zeng Y, Fang C, Cheng W, Li Y. Effect of TTLL12 on tubulin tyrosine nitration as a novel target for screening anticancer drugs in vitro. Oncol Lett 2020; 20:340. [PMID: 33123251 PMCID: PMC7583732 DOI: 10.3892/ol.2020.12203] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 09/14/2020] [Indexed: 12/13/2022] Open
Abstract
Nitrotyrosine, a structural analogue of tyrosine, is present in cells in pathological conditions and is incorporated into tubulin to form tubulin tyrosine nitration, which disrupts the normal function of microtubules. There is limited research on the functional aspects of tubulin tyrosine nitration in different types of tumor. In the present study, the effect of tubulin tyrosine nitration and tubulin tyrosine ligase like 12 (TTLL12) on the proliferation of SCC-25 cells was investigated. TTLL12-overexpressing cell lines were constructed and used to assess the effect of tubulin tyrosine nitration and TTLL12 on the proliferation of SCC-25 cells via western blotting, immunofluorescent and MTT assays. An TTLL12-stably overexpressing SCC-25 cell line and the enzyme-linked immunosorbent assay were used to establish a novel experiment in vitro for screening anticancer drugs targeting tubulin tyrosine nitration by assessing its sensitivity, specificity and repeatability, and using it to find an effective drug. The results demonstrated that the proliferative rate of the control cells was notably inhibited in the presence of nitrotyrosine compared with that of TTLL12-overexpressing cells. The results of the MTT assay revealed that the proliferation of TTLL12-silenced cells was significantly inhibited compared with that of the control group. The sensitivity, specificity and repeatability of the experiment were positive. It was found that nocodazole could have better anticancer effect than paclitaxel. Taken together, the results of the present study suggest that TTLL12 enhances SCC-25 cell survival in the presence of nitrotyrosine by disrupting nitration of the tyrosine residues of tubulin, and tubulin tyrosine nitration may be developed for the basic research of anticancer drugs.
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Affiliation(s)
- Lingli Xue
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Yan Zeng
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Chuan Fang
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Wei Cheng
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Yadong Li
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
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Sabeti Aghabozorgi A, Moradi Sarabi M, Jafarzadeh-Esfehani R, Koochakkhani S, Hassanzadeh M, Kavousipour S, Eftekhar E. Molecular determinants of response to 5-fluorouracil-based chemotherapy in colorectal cancer: The undisputable role of micro-ribonucleic acids. World J Gastrointest Oncol 2020; 12:942-956. [PMID: 33005290 PMCID: PMC7510001 DOI: 10.4251/wjgo.v12.i9.942] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Revised: 05/11/2020] [Accepted: 07/19/2020] [Indexed: 02/05/2023] Open
Abstract
5-flurouracil (5-FU)-based chemotherapy is the main pharmacological therapy for advanced colorectal cancer (CRC). Despite significant progress in the treatment of CRC during the last decades, 5-FU drug resistance remains the most important cause of failure in CRC therapy. Resistance to 5-FU is a complex and multistep process. Different mechanisms including microsatellite instability, increased expression level of key enzyme thymidylate synthase and its polymorphism, increased level of 5-FU-activating enzymes and mutation of TP53 are proposed as the main determinants of resistance to 5-FU in CRC cells. Recently, micro-ribonucleic acids (miRNA) and their alterations were found to have a crucial role in 5-FU resistance. In this regard, the miRNA-mediated mechanisms of 5-FU drug resistance reside among the new fields of pharmacogenetics of CRC drug response that has not been completely discovered. Identification of the biological markers that are related to response to 5-FU-based chemotherapy is an emerging field of precision medicine. This approach will have an important role in defining those patients who are most likely to benefit from 5-FU-based chemotherapy in the future. Thereby, the identification of 5-FU drug resistance mechanisms is an essential step to predict and eventually overcome resistance. In the present comprehensive review, we will summarize the latest knowledge regarding the molecular determinants of response to 5-FU-based chemotherapy in CRC by emphasizing the role of miRNAs.
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Affiliation(s)
| | - Mostafa Moradi Sarabi
- Department of Biochemistry and Genetics, School of Medicine, Lorestan University of Medical Sciences, Khorramabad 381251698, Iran
| | - Reza Jafarzadeh-Esfehani
- Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad 1394491388, Iran
| | - Shabnaz Koochakkhani
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas 7919915519, Iran
| | - Marziyeh Hassanzadeh
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas 7919915519, Iran
| | - Soudabeh Kavousipour
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas 7919915519, Iran
| | - Ebrahim Eftekhar
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas 7919915519, Iran
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